Female sexuality is an desire, arousal, orgasm or pain, are estimated to afflict 30-50 percent of women in the United States. These disorders may be chronic, progressive, age-related and adversely affect quality of life and interpersonal relationships. In particular, sexual arousal disorder, has been linked to age, menopause, hysterectomy and vascular risk factors. Overall clinical management of afflicted patients has been primarily psychologically and hormonally-based. There has been limited research attention to the physiologically or medically-based conditions which adversely affect the female sexual arousal response. Recently, increasing numbers of afflicted women are utilizing "off-label" oral vasoactive agents for treatment of diminished genital swelling/lubrication responses in the absence of such physiologic and clinical trial data, suggesting demand for improved female sexual health care management. There is a need to broaden understanding of the pathophysiologic mechanisms of female sexual dysfunction. The overall goal of this proposal is to define the physiological mechanisms underlying the arousal component of the female sexual response. Specifically, they will investigate the physiologic mechanisms of clitoral and vaginal smooth muscle contractility which contribute to clitoral and vaginal engorgement during genital swelling/lubrication responses. To accomplish this goal, they have developed several experimental systems including: I) an in vivo animal model to record physiologic and hemodynamic changes in the clitoris and vagina following pelvic nerve stimulation, ii) in vitro organ baths of clitoral and vaginal tissue to investigate mechanisms involved in the modulation of smooth muscle contractility and iii) primary cultures of human and animal clitoral and vaginal smooth muscle cells to examine signal transduction pathways underlying smooth muscle tone. The Specific Aims of this proposal are to investigate: 1) neurogenic mechanisms modulating clitoral and vaginal smooth muscle contractility, 2) signal transduction pathways by which alpha-adrenergic receptors, nitric oxide and VIP modulate smooth muscle function, 3) the activity, in vivo, of alpha-adrenergic antagonists, VIP and nitric oxide on clitoral and vaginal hemodynamic response to pelvic nerve stimulation and 4) the role of estrogens in modulating vaginal and clitoral smooth muscle function. These studies should lead to new and useful information concerning physiological and pathophysiological mechanisms in female sexual arousal and to potentially improve diagnostic and treatment strategies for women suffering from sexual dysfunction.